Protein honeycombs engineered to control cell responses

January 29, 2021

A new protein structure can bend cells to its will. (Pixabay/Arek Socha)

Researchers created a new protein material that can influence cells for long periods of time by preventing them from retracting their receptors. The self-assembling hexagonal lattices they designed could improve medical treatments and pave the way for other synthetic structures that also manipulate cell behavior.

Cells interact with their environment with an array of receptors on their outer membranes, which receive information by binding with hormones, drugs or other compounds. To remain sensitive to their surroundings, cells absorb receptors that are bound to a signaling molecule and deconstruct them before deploying replacement receptors. 

This can limit the impact of drug treatments, which can influence cells for only as long as they are bound to receptors.

“This tendency of cells to internalize receptors likely lowers the efficiency of immunotherapies,” said Emmanuel Derivery, a professor of molecular biology at Cambridge University and a senior author of the study. “Indeed, when antibody drugs bind their target receptors and then become internalized and degraded, more antibody must always be injected.”

In a paper published in Nature, scientists from Cambridge and the University of Washington presented a solution based in protein engineering: a hexagonal lattice that extends the time receptors are active. It is one of the first ordered two-dimensional structures to be made from two different protein components, a fact that grants it advantages over one-component peers, according to the researchers.

Ariel Ben-Sasson, a postdoctoral fellow at Washington and the study’s lead author, emphasized the importance of designing a structure that is relatively easy to create.

“Not only (do) you want to design a specific structure; you also want to design its assembly process,” said Ben-Sasson, who researches organic electronics. “This is the most important part, because if you don't design the assembly process, then you cannot control it and the material is usually not useful.”

Ben-Sasson and his colleagues arrived at a simple way to build their honeycomb-shaped molecules: Mix two solutions, with each one containing a protein component of the lattice. The synthetic building blocks — a three-pronged protein forming the corners and a straight one connecting them — were easy to create and self-assembled into the hexagonal pattern in minutes.

Using two proteins made the material easier to create and handle than if it were made from a single repeated component, which would likely begin assembling before application and become more difficult to handle, according to the researchers. They reported that the organization of two proteins into a hexagonal structure has not been found in nature.

The lattices were interlaced with signaling molecules and tested on multiple kinds of cell receptors. They “almost completely shut down” the retraction of the receptors for hours or days, the researchers wrote, being most effective when assembled into relatively large structures that spanned many receptors. 

The protein honeycomb’s secret was in its flatness, which made them much more challenging for cells to absorb than many other biological compounds and their rounder shapes.

The technology could be used to augment drug treatments by helping them stay active for longer, and, "The ability to assemble designed proteins around cells opens up new approaches for reducing immune responses to introduced cells, for example in therapy for type 1 diabetes,” the scientists wrote.

Ben-Sasson — who highlighted the value of interdisciplinary collaboration between engineers and biologists for the research — said the paper is part of a larger effort to learn about the powerful yet enigmatic processes behind creating proteins and other natural compounds, which could be harnessed to create new materials with similar complexity and usefulness.

“We want to understand more and more principles of how to create extremely complex structures,” the Washington researcher said, “not because they're complex, just because the functionality that they serve is very unique.”

Creating structures with multiple components rather than one could also lead to more useful functions, he and his colleagues wrote in the paper.

Ben-Sasson said that developing better materials has been an essential part of human progress, dating back to the Stone, Bronze and Iron ages.

“I don’t know of any revolution in human history that was not related to materials,” he said.

The article, “Design of biologically active binary protein 2D materials,” was published Jan. 6 in Nature. The authors of the study were Ariel Ben-Sasson, William Sheffler, Matthew Johnson, Logeshwaran Somasundaram, Justin Decarreau, Fang Jiao, Jiajun Chen, James De Yoreo, Justin Kollman, Hannele Ruohola-Baker and David Baker, University of Washington; Joseph Watson, Alice Bittleston, Ioanna Mela and Emmanuel Derivery, MRC Laboratory of Molecular Biology; Andrew Drabek, Sanchez Jarrett and Stephen Blacklow, Harvard University; Clemens Kaminski, University of Cambridge; and Greg Hura, Lawrence Berkeley National Laboratory. The lead author was Ariel Ben-Sasson.

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